Protein tyrosine kinases have been identified as key players in cellular regulation. They are involved in immune, endocrine, and nervous system physiology and pathology and thought to be important in the development of many cancers. Tyrosine kinases catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine hydroxyls of proteins. It modulates a wide variety of cellular events, including differentiation, growth, metabolism and apoptosis.
Protein tyrosine kinases represent a diverse and rapidly expanding superfamily of protein, including both transmembrane receptor tyrosine kinases and soluble cytoplasmic enzymes also known as nonreceptor tyrosine kinases. Receptor-type protein tyrosine kinases, which have a transmembrane topology, have been studied extensively. The binding of a specific ligand to the extracellular domain of receptor protein tyrosine kinases is thought to induce receptor dimerization and phosphorylation of their own tyrosine residues. The intracellular, cytoplasmic, non-receptor protein tyrosine kinases may be broadly defined as those protein tyrosine kinases, which do not contain a hydrophobic, transmembrane domain. Within this broad classification, one can divide the known cytoplasmic protein tyrosine kinases into four distinct morphotypes: the SRC family, the FES family, the JAK family and the ABL family. While distinct in their overall molecular structure, each of the members of these morphotypic families of cytoplasmic protein tyrosine kinases share non-catalytic domains in addition to sharing their catalytic kinase domains.
The ABL proto-oncogene normally encodes a protein with tyrosine kinase activity. This activity is augmented in cells carrying bcr-abl hybrid genes. The BCR-ABL protein tyrosine kinase oncoprotein may transform cells via changes in enzyme activity and/or altering of noncovalent protein-protein interactions. The gene encoding the BCR-ABL oncoprotein is a chimeric oncogene generated by the translocation of sequences from the cABL protein tyrosine kinase on chromosome 9 into BCR sequences on chromosome 22 (reviewed in Kurzock et al., 1988, N. Enql. J. Med. 319:990-998, and Rosenberg et al., 1988, Adv. in Virus Res. 35:39-81). The BCR-ABL oncogene has been implicated in the pathenogenesis of Philadelphia chromosome (Ph@1) positive human leukemias. Namely, the Ph@1 chromosome is found in at least 90 to 95 percent of cases of chronic myelogenous leukemia (CML), which is a clonal cancer arising from the neoplastic transformation of hematopoietic stem cells (Fialkow et al., 1977, Am. J. Med. 63:125-130), and is also observed in approximately 20 percent of adults with acute lymphocytic leukemia (ALL), 5 percent of children with ALL, and 2 percent of adults with acute myelogenous leukemia (AML) (Whang-Peng et al., 1970, Blood 36:448-457; Look, A. T., 1985, Semin. Oncol. 12:92-104). The BCR-ABL gene produces two alternative chimeric proteins, P210 BCR-ABL, and P185 BCR-ABL, which are characteristic of CML and ALL, respectively. Further, it has recently been directly demonstrated that the BCR-ABL gene product is the causative agent in CML (Skorski et al., 1993, J. Clin Invest. 92:194-202; Snyder et al., 1993, Blood 82:600-605).
Two major types of bcr-abl translocations are known, characterized by two different bcr-abl junctions. One translocation is between bcr exon 2 and abl exon 2, while another translocation is between bcr exon 3 and the same abl exon 2 (Shtivelman et al., Cell 47, 277-284 (1986)). The two types of junction have been referred to as the “L-6” (or “b2a2”) and “K-28” (or “b3a2”) junctions, respectively. The alternative splicing from two bcr-abl exons to the abl coding sequence results in two different bcr-abl fusion proteins, one including the 25 amino acids encoded by bcr exon 3 and one which lacks those amino acids. One or both of these junctions is detected in Ph@1 -positive CML patients (Shtivelman et al., Blood 69, 971 (1986)).
It has now been founded that phenylaminopyrimidine derivatives of formula (I), described below, are a new class of compounds that have advantageous pharmacological properties and inhibit the activity of tyrosine kinases, for example, the activity of the BCR-ABL tyrosine kinase, the activity of other receptor tyrosine kinases, such as PDGF.
On the basis of the described properties, is thus suitable for the treatment of Bcr-Abl-positive cancer and tumor diseases, such as leukaemias (especially chronic myeloid leukaemia and acute lymphoblastic leukaemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukaemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells) as well as Gastrointestinal Stromal Tumors (GIST). A compound of formula I may be used not only as a tumor-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma, and fibrosis, as well as for the protection of stem cells, for example to combat the haemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. It may especially be used for the treatment of diseases which respond to an inhibition of the PDGF receptor kinase.
In addition, a compound of formula I prevents the development of multidrug resistance in cancer therapy with other chemotherapeutic agents or abolishes a pre-existing resistance to other chemotherapeutic agents. Also regardless of the effect described hereinbefore, a compound of formula I may be used to advantage in combination with other antitumor agents.
Examples of phenylaminopyrimidine derivatives that are similar in structure to those of the present invention are disclosed in the following patent applications: EP 0564409, WO 9509847, WO 9509851, WO 9509852, WO 9509853, WO 0222597.